Chapter Three - Intestinal Stem Cells and Their Defining Niche

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Abstract

The intestinal epithelium is a classic example of a rapidly self-renewing tissue fueled by dedicated resident stem cells. These stem cells reside at the crypt base, generating committed progeny that mature into the various functional epithelial lineages while following a rapid migratory path toward the villi. Two models of intestinal stem cell location were proposed half a century ago and data have been presented in support of both models, dividing the scientific community. Molecular markers have been identified and validated using new techniques such as in vivo lineage tracing and ex vivo organoid culture. The intestinal stem cell niche comprises both epithelial cells, in particular the Paneth cell, and the stromal compartment, where cell-associated ligands and soluble factors regulate stem cell behavior. This review highlights the recent advances in identifying and characterizing the intestinal stem cells and their defining niche.

Section snippets

The Mammalian Small Intestine

The mammalian small intestine functions to complete digestion, absorb nutrients from food passing through from the stomach, and also forms a protective barrier against pathogens in the intestinal lumen. These functions are performed by a simple columnar epithelium lining the small intestine that is ordered into invaginations, known as crypts of Lieberkühn, interspersed with finger-like protrusions, called villi, which vastly expand the absorptive surface area of the gut (Marshman, Booth, &

The long search for the elusive intestinal stem cells

Almost 50 years ago, two models of intestinal stem cell (ISC) location were proposed: the classical + 4 model and the stem cell zone model. Since then, data have been presented in support of both models and until today, scientists are somewhat divided over the true identity of the stem cells.

The classical model (+ 4 model) of intestinal crypt stem cells was first proposed after rudimentary cell tracking experiments suggested a cell of origin situated directly above the Paneth cells in the “+4

Characterizing Stem Cell Behavior During Homeostasis and Disease

Mammalian stem cell populations are thought to be maintained in a largely quiescent state, possibly to preserve their long-term proliferation potential and to guard against DNA replication errors during cell division (Fuchs, 2009). For example, in the hematopoietic stem cell (HSC) system, dormant LRCs exhibit long-term regenerative potential whereas more actively dividing HSCs demonstrate only shorter term repopulation potential (Wilson et al., 2008). In the hair follicle, which undergoes

Reconciling the Opposing ISC Models

As discussed earlier, the intestinal crypts are thought to harbor independent pools of cycling stem cells marked by Lgr5 (the CBC cells) and relatively quiescent stem cells marked by Bmi1, mTert, and Lrig1 (+ 4 cells). In an attempt to directly isolate the quiescent + 4 cells from the small intestine, independent groups employed an H2B-YFP pulse-chase model to mark LRCs in the crypts (Buczacki et al., 2013, Roth et al., 2012). Expression profiling of the isolated LRC population revealed a robust

Concept of a niche

The term “stem cell niche” was first coined by Ray Schofield in 1978 to describe the association of a stem cell with other cells, which determine its behavior (Schofield, 1978). The postulation of a microenvironment necessary for maintenance of stem cells has gained traction over the years with generation of data that indicate that a stem cell niche may comprise cells or cells together with extracellular matrix, and act as a source of growth factors that regulate self-renewal and proliferation (

Studying ISCs Ex Vivo

Efforts to grow intestinal crypts ex vivo by either culturing pieces of intestinal tissue or growing crypts from single stem cells facilitate the detailed study of specific niche components as a prerequisite to understanding their in vivo function. Apart from the “mini-gut” organoid culture system described earlier (Sato et al., 2009), other systems include one that incorporates an air–liquid interface together with underlying stromal elements that allowed for prolonged intestinal epithelial

Conclusion

Our current understanding of the intestinal crypt is that rapidly proliferating stem cells reside at the crypt base flanked by Paneth cells. These cells express markers such as Lgr5, Ascl2, Olfm4, Rnf43, Znrf3, Smoc2, and Troy. More quiescent stem cells are generally detected at the + 4 position and these act as a reserve population that is activated to proliferate in response to injury. While the Paneth cells work in conjunction with the surrounding mesenchyme to provide key niche signals to

Acknowledgments

We thank all the members of the Barker lab, and the Agency for Science, Technology and Research (A*STAR) for funding.

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